Breakthroughs in Osimertinib and Three Other Investigational Drugs by Ascentage Pharma Revealed at AACR Annual Meeting

In a significant development, Ascentage Pharma (6855.HK) announced the unveiling of three preclinical research advancements during the 2024 American Association for Cancer Research (AACR) Annual Meeting. These breakthroughs involve Ascentage's proprietary first-in-class drug, Osimertinib (marketed as Tagrisso®), as well as the MDM2-p53 inhibitor APG-115, the FAK/ALK/ROS1 triple kinase inhibitor APG-2449, and the embryonic ectoderm development inhibitor APG-5918. This year's AACR Annual Meeting took place from April 5th to April 10th in San Diego, USA.

Ascentage Pharma, a leading biopharmaceutical company, made an exciting announcement during the 2024 AACR Annual Meeting regarding their innovative oncology pipeline. The company shared significant progress in three preclinical studies, shedding light on the potential of their novel drugs to revolutionize cancer treatment.

One of the focal points of Ascentage's research is Osimertinib, a groundbreaking multikinase inhibitor. Osimertinib demonstrated exceptional antitumor activity in succinate dehydrogenase (SDH)-deficient neoplasms. SDH-deficient tumors are characterized by the inactivation of any one of the four components of the mitochondrial SDH complex (SDH A-D), resulting in the loss of SDHB immunohistochemical expression. The accumulation of succinate due to SDH deficiency plays a crucial role in the development of various tumors, including gastrointestinal stromal tumors (GIST), paragangliomas, pheochromocytomas, renal cell carcinomas, pituitary adenomas, and pancreatic neuroendocrine tumors.

Patients with SDH-deficient tumors, especially GIST, have a poor prognosis, and the efficacy of approved tyrosine kinase inhibitors (TKIs) in these patients is limited. However, Osimertinib, a multitargeted kinase inhibitor, has shown promising results in an ongoing Phase I clinical trial for the treatment of patients with dSDH-type GIST. The research evaluated the antitumor activity of Osimertinib in preclinical models of dSDH-type tumors and primary dSDH GIST tumor cells, as well as exploring its potential mechanism of action (MOA). The findings revealed that Osimertinib exhibited stronger antitumor activity in dSDH cell lines and ex vivo models of human dSDH-type GIST than other TKIs. This novel multikinase inhibitor exerts its antitumor activity by modulating several critical signaling pathways involved in dSDH-type tumor formation, including cell hypoxia, angiogenesis, apoptosis, cell proliferation, and cell survival.

Another noteworthy advancement presented by Ascentage Pharma at the AACR Annual Meeting focused on the synergistic inhibition of tumor growth in preclinical models of prostate cancer (PCa) through the combination of the embryonic ectoderm development (EED) inhibitor APG-5918 (EEDi-5273) and the MDM2 inhibitor alrizomadlin (APG-115). Prostate cancer is one of the most common malignancies in elderly males, and while androgen deprivation therapy (ADT) in combination with androgen receptor (AR) inhibitors is commonly used as an initial treatment for advanced PCa, most patients eventually develop castration-resistant prostate cancer (CRPC) and urgently require novel therapeutic approaches. Dysregulation of the polycomb repressive complex 2 (PRC2) is prevalent in PCa and is associated with poor prognosis. PRC2 mediates trimethylation of histone H3 lysine 27 (H3K27me3), an epigenetic mark that inhibits gene transcription. EED, a core component of PRC2, directly interacts with H3K27me3 and plays a crucial role in tumor growth.

The preclinical study demonstrated that the combination of APG-5918 and APG-115 synergistically inhibited tumor growth in PCa models. These findings highlight the potential of targeting EED and MDM2 as a promising therapeutic strategy for prostate cancer.

Ascentage Pharma's participation in the 2024 AACR Annual Meeting showcased significant advancements in their investigational drugs, including Osimertinib, APG-115, APG-2449, and APG-5918. These findings provide a solid foundation for the clinical development of these novel agents, offering hope for improved treatment options for patients with SDH-deficient tumors and prostate cancer. Ascentage Pharma's innovative approach and commitment to advancing cancer research are poised to make a lasting impact on the field of oncology.